title: Characterization of a novel proinflammatory effect mediated by BK and the kinin B₂ receptor in human preadipocytes.
abstract: Obesity and adipose tissue contribute to local and systemic inflammation. However the role of the inflammatory mediator bradykinin (BK) in this context is not known. We therefore evaluated the effect of BK on adipokines secretion in human preadipocytes during the course of differentiation and characterized the receptors involved. Results obtained from antibody array and ELISA experiments showed that several adipokines are released by human preadipocytes under basal conditions while BK specifically stimulated the production of interleukin(IL)-6 and IL-8. The effect of BK diminished with the progression of differentiation, being almost inactive on adipocytes. In preadipocytes, BK also induced a rapid and transient [Ca²⁺](i) mobilization, a rapid and sustained increase in ERK1/2 activation and enhanced forskolin-stimulated cAMP accumulation. BK was without effect on cell proliferation and viability as assessed by bromodeoxyuridine incorporation, WST-1 conversion, or lactate dehydrogenase leakage and was without effect on adipogenesis as measured by triglyceride accumulation, GPDH activity and leptin release. The B₁ receptor agonist, Lys-[des-Arg⁹]-BK, displayed poor activity or was without effect while overall BK effects were prevented by the selective B₂ receptor antagonist, fasitibant chloride, but not by the B₁ selective antagonist, Lys-[Leu⁸][des-Arg⁹]-BK. Immunoblot analysis and immunofluorescence studies showed that the kinin B₂ receptor was essentially expressed at the beginning of the differentiation program. In conclusion, human preadipocytes expressed kinin B₂ receptors linked to multiple signaling pathways, IL-6 and IL-8 production, and BK proinflammatory response in adipose tissue could be prevented by fasitibant chloride.
authors.affiliation: Pharmacology Department, Menarini Ricerche SpA, Via Rismondo 12A, 50131 Florence, Italy. chimfarm@menarini-ricerche.it
authors.forename: Rose-Marie
authors.initials: RM
authors.lastname: Catalioto
authors.forename: Claudio
authors.initials: C
authors.lastname: Valenti
authors.forename: Luca
authors.initials: L
authors.lastname: Liverani
authors.forename: Sandro
authors.initials: S
authors.lastname: Giuliani
authors.forename: Carlo Alberto
authors.initials: CA
authors.lastname: Maggi
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D054392:Adipokines / Q000378:metabolism*; D001920:Bradykinin / Q000378:metabolism* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis; D016207:Cytokines / Q000378:metabolism*; D005993:Glycerolphosphate Dehydrogenase / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D043782:Receptor, Bradykinin B2 / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D054392:Adipokines; D016207:Cytokines; D015850:Interleukin-6; D016209:Interleukin-8; D020738:Leptin; D043782:Receptor, Bradykinin B2; D014280:Triglycerides; D000242:Cyclic AMP; D005993:Glycerolphosphate Dehydrogenase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D001920:Bradykinin; D002118:Calcium
keywords: 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate; ANGPTL-4; Adipokines secretion; Ang-1; Ang-2; BrdU; DAKD; DALKD; ERK(1/2); FCS; Fasitibant chloride; GPDH; HBSS; Hank's balanced salt solution; Human preadipocytes; IGFBP-2; IL; Kinin B(2) receptor; LDH; Lys-[Leu(8)][des-Arg(9)]-BK; Lys-[des-Arg(9)]-BK; MCP-1; MMP; PG; Proinflammatory cytokines; Sn-glycerol-3-phosphate dehydrogenase; TIMP; WST-1; [Ca(2+)]i; angiopoietin-1; angiopoietin-2; angiopoietin-related protein 4; bromodeoxyuridine; extracellular signal-regulated kinases 1 and 2; foetal calf serum; insulin-like growth factor binding protein-2; interleukin; intracellular calcium ion concentration; lactate dehydrogenase; matrix metalloproteinase; monocyte chemoattractant protein-1; prostaglandin; sTNFRI; sTNFRII; soluble tumor necrosis factor receptor type I; soluble tumor necrosis factor receptor type II; tissue inhibitor of metalloproteinases